Calcium phosphate-based cements (a.) H. Monma and T. Kanazawa, “Wet-Process Formation of Non-stoichiometric Hydroxyapatite from Tricalcium Phosphate,” Yogyo Kyokaishi, 86, 73-76, 1978, b.) W. E. Brown and L. C. Chow, “A New Calcium Phosphate Water Setting Cement”; pp. 352-77 in Cements Research Progress-1986, Edited by P. W. Brown. American Ceramic Society, Westerville, Ohio, 1987, c.) A. A: Mirtchi, J. Lemaitre, and E. Munting, “Calcium Phosphate Cements: Study of the beta-tricalcium Phosphate-Dicalcium Phosphate-Calcite Cements,” Biomaterials, 11, 83-88, 1990, d.) F. C. M. Driessens, J. A. Planell, et al., Bioceramics, 10, 279-82, 1997, e.) K. S. TenHuisen and P. W. Brown, “Formation of Calcium-Deficient Hydroxyapatite from alpha-Ca3(PO4)2,” Biomaterials, 19, 2209-17, 1998.) are conventionally prepared by mixing calcium phosphate powders of a special composition and a kneading liquid, such as distilled water, for example, in a mortar to obtain kneaded cement which may then be filled into or applied to a defective portion of bone (or tooth) using a syringe or spatula or hand and then allowed to cure.
Calcium phosphate-based cements are usually desired to be almost identical with the chemical composition of the inorganic component of bones or teeth, which is carbonated, deficient or stoichiometric “calcium hydroxyapatite.” However, in recent years with an increase in the number of animal studies performed with such materials, it is becoming more and more evident that the calcium hydroxyapatite bioceramic, when prepared synthetically or even when taken from bovine sources in highly porous forms (i.e., granules or blocks), has very low bioresorbability (M. T. Mushipe, P. A. Revell, and J. C. Shelton, “Cancellous Bone Repair using Bovine Trabecular Bone Matrix Particulates,” Biomaterials, 23, 365-370, 2002), and moreover, if it is stoichiometric (i.e., its Ca/P molar ratio being equal to 1.67) it almost doesn't take part in the bone remodelling processes which were initiated and performed by the bone cells in vivo.
Calcium phosphate-based cements when they are prepared by using calcium phosphate powder formulations which have a Ca/P molar ratio values higher than 1.50 (e.g., F. C. M. Driessens, M. G. Boltong, E. A. P. De Maeyer, R. M. H. Verbeeck, and R. Wenz, “Effect of temperature and immersion on the setting of some calcium phosphate cements,” J. Mater. Sci. Mater. Medic., 11, 453-57, 2000) do also show reduced levels of resorbability (as compared to calcium phosphate cements (e.g., U.S. Pat. No. 6,117,456) of lower Ca/P molar ratios) when implanted in vivo.
However, the Ca/P molar ratio of calcium phosphate-based cements do not alone dictate the extent of in vivo resorbability of these. Together with the appropriate adjustment of the overall Ca/P ratio, the proper choice of the calcium phosphate compounds (in an order of decreasing in vitro solubility at neutral pH values: TTCP (Ca4(PO4)2O), alpha-TCP (Ca3(PO4)2), MCPM (Ca(H2PO4)2·H2O), beta-TCP, Ca2P2O7, DCPD (CaHPO4·2H2O), DCPA (CaHPO4), or HA (Ca10(PO4)6(OH)2)) to be used in the design of cements becomes the crucial factor in tailoring the resorbability of a new cement.
In selecting the calcium phosphate compounds (either from the binary system of CaO—P2O5 or from the ternary system of CaO—P2O5—H2O) to form a cement powder out of those, utmost care and priority must also be given to the in vitro/in vivo solubility (and the rate of hydrolysis of those in media similar to human plasma) of the candidates under consideration.
Calcium phosphate cements for living bodies have an advantage that most of them transform into a bioactive hydroxyapatite (also known as “apatitic tricalcium phosphate,” Ca9(HPO4)(PO4)5OH) upon hardening, and hence result in a hardened cement having excellent bioaffinity. Many of the already known calcium phosphate cements for living bodies comprise tetracalcium phosphate (TTCP, Ca4(PO4)2O) as the main component. For example, U.S. Pat. No. 4,612,053 and EP No. 1172076 disclose cements comprising tetracalcium phosphate and dicalcium phosphate anhydrous (DCPA, CaHPO4) as the main components, whereas the U.S. Pat. No. 5,525,148 describes the preparation of a series of calcium phosphate cements which do not contain any TTCP. It is also known that the hardening properties (i.e., setting times (typically measured in the dry state) and final compressive strengths achieved following immersion in pseudo or real physiological fluids) of these calcium phosphate cements widely vary also depending on the amount of liquid employed in the step of kneading. That is, the hardening time is shortened while the strength of the hardened body is elevated with a decrease in the kneading liquid employed.
The most popular TTCP-containing cement (whose secondary component being the acidic calcium phosphate, MCPM: Ca(H2PO4)2·H2O) is known under the commercial name of “Norian SRS,” and it has a compressive strength in the vicinity of 40 MPa, according to its manufacturer (Norian Corporation). This cement has a Ca/P molar ratio slightly greater than 1.50. Its in vivo resorbability still requires the disclosure of animal and clinical tests from independent sources.
U.S. Pat. No. 6,117,456 discloses the preparation of a highly resorbable (complete in vivo resorption in less than a year) cement of the name alpha-BSM (which is marketed in Europe (by Biomet-Merck) under the name of “BIOBON®”). This cement consists of two powder components, (i) poorly crystalline calcium phosphate (major phase), and (ii) well-crystallized DCPD (Brushite, CaHPO4·2H2O). BIOBON® has a Ca/P molar ratio less than 1.50. Although it is major, poorly crystalline calcium phosphate component reacts quite rapidly (started within the first 24 hours, and continues with the passage of time) to form apatitic tricalcium phosphate (Ca9(HPO4)(PO4)5OH), the full resorption of the crystalline component takes significantly longer to take place. BIOBON® (or alpha-BSM), which is kneaded with a simple saline solution to form its paste, suffers from extremely low compressive strength values (in the vicinity of 10 to 15 MPa) upon full setting, and this severely limits its usage mainly to “non-load-bearing” places and applications.
U.S. Pat. No. 5,152,836 describes a calcium phosphate cement (again with a Ca/P molar ratio slightly greater than 1.50) composed of alpha-TCP (75 wt %), TTCP (18 wt %), DCPD (5 wt %), HA (2 wt %), kneaded into a paste with a relatively concentrated aqueous solution of chondroitin sulphate and sodium succinate. This cement has been in the market under the commercial name of BIOPEX®) (Mitsubishi Material Co.). It is claimed to achieve a compressive strength of 60 to 90 MPa. Little is known about its resorbability, but it is claimed by its manufacturer to resorb quite fast (around 50% in few weeks).
The newest calcium phosphate cement commercially available on the market is known as CALCIBON® (produced and marketed by Biomet-Merck) with a Ca/P molar ratio of 1.55, and it consists of a mixture of alpha-TCP (58-60 wt %), DCPA.(26-27 wt %), CaCO3 (12-13 wt %), and HA (2%). It has a compressive strength over the range of 50-60 MPa, and in the bulk form (i.e., without any significant macroporosity) it is not as fast-resorbable as BIOBON®. High compressive strength calcium phosphate cements are nevertheless still suitable for the repair of bone cavities or defects in load-bearing places of the living bodies.
Alpha-TCP, alone, is known to easily hydrolyze in vitro or in vivo directly into calcium-deficient hydroxyapatite (K. S. TenHuisen and P. W. Brown, “Formation of Calcium-Deficient Hydroxyapatite from alpha-Ca3(PO4)2,” Biomaterials, 19, 2209-17, 1998), and the Ca/P molar ratios in a wide family of “calcium-deficient hyroxyapatites” can take values over the range of 1.3 to 1.65. When these values are in excess of 1.50, and when they become progressively closer to that of stoichiometric hydroxyapatite (1.67), the resorbability of the implants is observed to decrease. On the other hand, if the formed calcium-deficient hydroxyapatites (as a result of the setting reaction) also contain alkali elements like Na and K, then the resorbability of the cements would also increase (F. C. M. Driessens, M. G. Boltong, E. A. P. de Maeyer, R. Wenz, B. Nies, and J. A. Planell, “The Ca/P Range of Nanoapatitic Calcium Phosphate Cements,” Biomaterials, 23, 4011-17, 2002). The intentional doping of crystallographic Ca-sites in the newly forming calcium-deficient hydroxyapatite microstructure (which is typically imaged in electron microscope micrographs with microflakes or microneedles forming on the alpha-TCP grains) with such alkali elements leads to the generation of vacancies, and carbonate ion (CO32−) substitutions in the hydroxyl sites and the phosphate ion sites, respectively. It also needs to be remembered hereby that the human bones contain around 1.6 wt % Na and K ions.
The primary powder components (i.e., alpha-TCP and TTCP) for almost all of the commercially available calcium phosphate cements, with the only exception of BIOBON®, have been prepared by solid-state reactive firing (SSRF) at high temperatures (in excess of 1350° C.). The use of such high temperatures during production inescapably lead to hard, sintered products with grain sizes mostly in excess of 80 to 100 μm, and therefore those components are needed to be grinded with high-energy mills, first, into a fine powder before their use in the cement formulations. High energy milling is generally performed for at least one hour in industrial rotating mills having hard (scratch-resistant) inner linings and hard balls, which can be made from agate or ceria-stabilized zirconia. Typically, the balls fill 20-25% of the volume of the mill and impact the material as the mill turns. These mills can increase the surface temperature of the individual particles and even cause undesirable mechanochemical reactions.
Fine powders (less than 30 μm) are strictly required in the calcium phosphate cement formulations in order to achieve higher rates of in vivo bioreactivity and biointegration with the ingrowing bone into the repair site. SSRF practices and the follow-up grinding operations naturally increase the costs of manufacturing of such cements.